Psoriasis is a chronic skin disease, characterized by scaling and inflammation. Psoriasis affects 1.5 to 2 percent of the United States population, or almost 5 million people. It occurs in all age groups and about equally in men and women. People with psoriasis suffer discomfort, restricted motion of joints, and emotional distress. When psoriasis develops, patches of skin thicken, redden, and become covered with silvery scales, referred to as plaques. Psoriasis most often occurs on the elbows, knees, scalp, lower back, face, palms, and soles of the feet. The disease also may affect the fingernails, toenails, and the soft tissues inside the mouth and genitalia. About 10 percent of people with psoriasis have joint inflammation that produces symptoms of arthritis.
When skin is wounded, a wound healing program is triggered, also known as regenerative maturation. Lesional psoriasis is characterized by cell growth in this alternate growth program. In many ways, psoriatic skin is similar to skin healing from a wound or reacting to a stimulus such as infection, where the keratinocytes switch from the normal growth program to regenerative maturation. Cells are created and pushed to the surface in as little as 2-4 days, and the skin cannot shed the cells fast enough. The excessive skin cells build up and form elevated, scaly lesions. The white scale (called “plaque”) that usually covers the lesion is composed of dead skin cells, and the redness of the lesion is caused by increased blood supply to the area of rapidly dividing skin cells.
Human epidermal keratinocytes express several adhesive receptors that belong to the integrin family of α/β heterodimers. Several of the keratinocyte integrins share a common β1 subunit. β1 integrins not only mediate keratinocyte adhesion to extracellular matrix proteins, but also play a role in intercellular adhesion, lateral migration, stratification, proliferation and the regulation of terminal differentiation. Integrin expression is largely confined to the basal, proliferative, layer of keratinocytes in normal adult skin, although in psoriatic lesions suprabasal keratinocytes co-express integrins. Suprabasal integrin expression has also been noted in eczema and lichen planus.
The chronic skin inflammation of psoriasis is associated with hyperplastic epidermal keratinocytes and infiltrating mononuclear cells, including CD4+ memory T cells, neutrophils and macrophages. Because of this highly mixed inflammatory picture and the resulting complex interrelationships between these different cells, it has been very difficult to dissect the mechanisms that underlie the induction and progression of the disease.
The instigating factors for psoriasis are poorly defined, although it evident that it is a T cell-mediated autoimmune condition. T cells are present throughout the epidermis and at a markedly high density on the dermal side of the epidermal-dermal junction. Within the epidermis, CD8+ cytotoxic T cells are more highly represented than CD4+ helper T cells. Activated T lymphocytes elaborate factors that drive the character of the psoriatic plaque. Psoriasis is considered a multi-gene disease although disease expression is due in part to environmental factors. Physical trauma, emotional stress, infection or certain medications may contribute to the psoriatic condition. The genetic association with psoriasis is strongest with the major histocompatibility complex (MHC) Class I allele HLA-Cw6 and to a lesser extent the MHC Class II allele HLA-DR7. This observation suggests that psoriasis pathogenesis may result from the recognition of a local peptide antigen presented by resident skin cells in the context of MHC Class I molecules to auto-reactive CD8+ T cells.
Although psoriasis is not life threatening, the social stigma and reduction in quality of life associated with disease are profound issues for these patients and their families. Currently, there is no long-term cure for psoriasis. Established anti-psoriasis therapies have been grouped into suppressive and remittive types. Suppressive therapies include coal tar preparations (natural coal tar or the distillate anthralin), topical corticosteroids, mechanical treatments to remove scale, and antimetabolites such as methotrexate. For remittive therapy, the photosensitizing drug, psoralen, combined with long wavelength ultraviolet light (PUVA), and synthetic retinoids or coal tar derivatives also is used. While mild to moderate cases can be treated somewhat effectively, more extensive cases are difficult and tend to be resistant to either topical therapy or ultraviolet phototherapy. Moreover, systemic use of traditional antipsoriatic drugs, or prolonged use of topical steroids, can lead to undesirable side effects or rebound worsening of psoriasis.
In particular, safety concerns for the patient with psoriasis, essentially a benign disorder, have been identified regarding the prolonged use of UVB and PUVA therapies. Psoralens intercalate within the DNA double helix and instigate DNA damage upon UVA irradiation. PUVA therapy is associated with increased risk for squamous cell carcinoma and malignant melanoma. PUVA-associated cancer risk increases with the number of treatments given. In addition, PUVA may increase skin cancer risk for patients who have a history of exposure to agents including ionizing radiation, methotrexate or arsenic as well as previous occurrences of basal or squamous cell carcinoma. UVB light, long recognized as a carcinogenic component of sunlight, is a standard anti-psoriasis therapy. UVB light directly interacts with DNA and is a potent carcinogen in animal systems.
The further development of treatments for psoriasis is of great interest.